The main objectives of this research proposal are to identify the B cell precursors of IgG autoantibodies associated with a human virus infection and to understand the mechanism by which they are activated. IgG autoantibodies are found in many human viral infections, but their origins are unknown. The specific focus of this proposal is on IgG autoantibodies that are uniquely associated with HIV-1 infection in humans. They are directed against a cell surface antigen termed CD43, a sialoglycoprotein expressed by virtually all leukocytes. There is evidence to suggest that IgG anti-CD43 autoantibodies in humans are derived from B cells similar to anergic B cells that have been identified in transgenic mice. Three principal features of murine anergic B cells are: (a) they express immunoglobulin receptors for endogenous antigens, (b) they are functionally inactive and unable to respond to self antigens, (c) they can escape from anergy if provided with T cell help. We plan to determine if anergic human B cells are precursors of the B cells that make IgG anti-CD43 autoantibodies in HIV-1 infection. (SPECIFIC AIM #1). To accomplish this, we will study the clonal derivation of IgG anti-CD43 autoantibodies associated with HIV-1 infection. The mechanism by which B cell tolerance is broken during the course of viral infection is unknown. In a murine model transgenic for the vesicular stomatitis virus G protein (VSV-G), there is evidence to suggest that anti- VSV-G B cells are released from their anergic state by receiving cognate signals from T cells that recognize other VSV proteins. We propose that a similar mechanism is operative in HIV-1 infection in humans, and perhaps in other human viral infections as well. We plan to determine if HIV-1- specific, CD4+ T cells can activate anti-CD43 B cells (SPECIFIC AIM #2). We know that such B cells exist in humans because we can detect IgG anti- CD43 autoantibodies in HIV-1-infected individuals. This model of autoimmunity is appealing because it links a foreign (viral) immunogen to autoimmunization against a specific self antigen (CD43). The importance of the proposed research is fourfold - it applies studies of B cell tolerance in transgenic mice to humans; it could provide evidence that anergic B cells in humans make autoantibodies; it could elucidate the B cell clonal origin(s) of IgG autoantibodies associated with HIV-1 infection, and; it could explain how virus infection breaks B cell tolerance to self.